Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients With Anaplastic Thyroid Cancer.

PURPOSE: Anaplastic thyroid cancer (ATC), an aggressive malignancy, is associated with a poor prognosis and an unmet need for effective treatment, especially for patients without BRAF mutations or NTRK or RET fusions. Lenvatinib is US Food and Drug Administration-approved for radioiodine-refractory differentiated thyroid cancer and has previously demonstrated activity in a small study of patients with ATC (n = 17). We aimed to further evaluate lenvatinib in ATC. METHODS: This open-label, multicenter, international, phase II study enrolled patients with ATC, who had ≥ 1 measurable target lesion, to receive lenvatinib 24 mg once daily. The primary end points were objective response rate (ORR) by investigator assessment per RECIST v1.1 and safety. Responses were confirmed ≥ 4 weeks after the initial response. Additional end points included progression-free survival and overall survival (OS). RESULTS: The study was halted for futility as the minimum ORR threshold of 15% was not met upon interim analysis. The interim analysis set included the first 20 patients. The full analysis set includes all 34 enrolled and treated patients. In the full analysis set, one patient achieved a partial response (ORR, 2.9%; 95% CI, 0.1 to 15.3). More than half of the evaluable patients experienced tumor shrinkage; three patients experienced a > 30% tumor reduction. The median progression-free survival was 2.6 months (95% CI, 1.4 to 2.8); the median overall survival was 3.2 months (95% CI, 2.8 to 8.2). The most common treatment-related adverse events (AEs) were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). No major treatment-related bleeding events or grade 5 treatment-related AEs occurred. CONCLUSION: The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted.

Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia.

OBJECTIVE: Evaluate the efficacy and safety of colesevelam hydrochloride in children with heterozygous familial hypercholesterolemia (heFH). STUDY DESIGN: This was a randomized, double-blind, 41-site study in 194 children aged 10 to 17 years (inclusive) with heFH (statin-naïve or on a stable statin regimen). After a 4-week stabilization period (period I), subjects were randomized 1:1:1 to placebo, colesevelam 1.875 g/d, or colesevelam 3.75 g/d for 8 weeks (period II). All then received open-label colesevelam 3.75 g/d for 18 weeks (period III), with follow-up 2 weeks later. The primary endpoint was percent change in low-density lipoprotein (LDL)-cholesterol from baseline to week 8. Secondary endpoints included percent change in other lipoprotein variables, including non-high-density lipoprotein (non-HDL)-cholesterol. Adverse events were also evaluated. RESULTS: At week 8, a significant difference from baseline in LDL-cholesterol was reported with colesevelam 1.875 g/d (-6.3%; P = .031) and colesevelam 3.75 g/d (-12.5%; P < .001) compared with placebo. Significant treatment effects were also reported for total cholesterol (-7.4%), non-HDL-cholesterol (-10.9%), HDL-cholesterol (+6.1%), apolipoprotein A-I (+6.9%), and apolipoprotein B (-8.3%) and a nonsignificant effect for triglycerides (+5.1%) with colesevelam 3.75 g/d compared with placebo at week 8. These treatment effects were maintained during period III. CONCLUSIONS: Colesevelam significantly lowered LDL-cholesterol levels in children with heFH.

A 50-week extension study on the safety and efficacy of colesevelam in adults with primary hypercholesterolemia.

BACKGROUND: Colesevelam is a bile acid sequestrant that differs structurally from traditional bile acid sequestrants, allowing it to bind bile acids with greater affinity. Studies have shown that colesevelam significantly reduces low-density lipoprotein cholesterol (LDL-C) levels and, in some cases, significantly increases high-density lipoprotein cholesterol (HDL-C) levels in adults with primary hypercholesterolemia. OBJECTIVE: To investigate the safety and efficacy of colesevelam in adults with primary hypercholesterolemia. STUDY DESIGN: This multicenter, open-label, titration-based extension study enrolled subjects who completed one of three multicenter, randomized, double-blind, placebo-controlled phase II studies with colesevelam. This study consisted of a 4-week washout/dietary stabilization period, a 50-week open-label treatment period, and a 2-week follow-up period. SETTING: Ten clinical centers within the US. SUBJECTS: Males and females 18 years of age or older who had completed a previous short-term (4- or 6-week) phase II clinical study with colesevelam. INTERVENTION: At week 0 (following a 4-week washout of all lipid-lowering medication), subjects initiated treatment with colesevelam at a dosage of 1.5 g/day. Colesevelam was uptitrated to a maximum dosage of 3.75 g/day as necessary to achieve a 15-30% reduction from baseline in LDL-C level. At week 12, an HMG-CoA reductase inhibitor (statin) or niacin (nicotinic acid) could be added if colesevelam 3.75 g/day was not sufficient to result in a 15-30% reduction from baseline in LDL-C level. MAIN OUTCOME MEASURE: The primary efficacy measure was the change in LDL-C level from baseline to week 50 across all treatment regimens. Secondary efficacy parameters included the change and percent change in total cholesterol, HDL-C, and triglyceride levels from baseline to week 50. There were three cohorts analyzed: (i) colesevelam monotherapy (included all subjects who received colesevelam monotherapy, regardless of dose); (ii) all treatment regimens (included all subjects who received colesevelam monotherapy or colesevelam plus low-dose statin or niacin therapy); and (iii) combination therapy (included only subjects who received colesevelam plus low-dose statin therapy). Two additional cohorts were also evaluated: (iv) maximum-dose colesevelam monotherapy (included only subjects who received colesevelam 3.75 g/day monotherapy); and (v) all maximum-dose colesevelam treatment regimens (included all subjects who received colesevelam 3.75 g/day, either as monotherapy or in combination with low-dose statin or niacin therapy). RESULTS: In total, 272 subjects were screened, 260 enrolled, and 186 completed the study. In total, 255 subjects were included in the intent-to-treat population. The maximum dosage of colesevelam (3.75 g/day) was taken by 50% of subjects (n = 94/188) at week 50; only 38 subjects received low-dose statin or niacin by study end. At week 50, LDL-C levels were significantly (p < 0.001) reduced from baseline across all treatment regimens (by 29.6 mg/dL [from 185.8 to 156.2 mg/dL; 15.0%]). Colesevelam also significantly reduced total cholesterol levels and significantly increased HDL-C and triglyceride levels across all treatment regimens (p < 0.001 for all). Drug-related adverse events were reported by 36.2% of subjects across all treatment regimens (and by 47.4% of subjects who received colesevelam plus low-dose statin or niacin therapy). CONCLUSION: In this study, colesevelam was found to be safe and effective for the management of LDL-C levels in adults with primary hypercholesterolemia.

Phase II Study of Eribulin Mesylate Administered Biweekly in Patients With Human Epidermal Growth Factor Receptor-2-negative Metastatic Breast Cancer.

BACKGROUND: Patients with human epidermal growth factor receptor-2-negative metastatic breast cancer (MBC), whose disease progressed on prior chemotherapy, have a poor prognosis. Eribulin, a microtubule dynamics inhibitor, extends overall survival in previously treated MBC. The most common adverse event associated with eribulin is neutropenia, which may result in dose interruptions or reductions. A modified biweekly dosing schedule of eribulin was assessed for efficacy as well as improvements in hematologic toxicity. PATIENTS AND METHODS: In this open-label, single-arm, multicenter, phase II study, previously treated (2-5 chemotherapy regimens for metastatic disease) patients with human epidermal growth factor receptor-2-negative MBC received intravenous eribulin 1.4 mg/m2 over 2 to 5 minutes on days 1 and 15 of each 28-day cycle. The primary study endpoints were objective response rate (ORR; complete response [CR] + partial responses [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]). RESULTS: Among 58 treated patients, the ORR was 12% (95% confidence interval [CI], 5%-24%), DCR (CR, n = 1; PR, n = 6; SD, n = 30) was 65%, and the median progression-free survival was 3.6 months (95% CI, 2.9-4.1 months). Grade 3 or 4 neutropenia was 31%; 50% of all patients, and 78% of patients with neutropenia (all grades), received hematopoietic growth-factor support. CONCLUSION: The efficacy and safety results obtained with a biweekly eribulin schedule in this phase II trial appear similar to those associated with the approved eribulin schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) reported in the EMBRACE study.

Effects of Subsequent Systemic Anticancer Medication Following First-Line Lenvatinib: A Post Hoc Responder Analysis from the Phase 3 REFLECT Study in Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Understanding the relationship between subsequent-line therapies and overall survival (OS) is important for maximizing OS for patients with hepatocellular carcinoma. OBJECTIVE: In this post hoc analysis, we investigated OS in lenvatinib- and sorafenib-treated patients from the REFLECT study, who then received subsequent anticancer medication during the survival follow-up period. METHODS: The follow-up period commenced at the first off-treatment visit after stopping the study medication and continued until study termination, withdrawal of consent, or death. OS and objective response rate were calculated for patients who did or did not receive poststudy anticancer medication for both treatment arms, as well as for the overall cohort. We investigated the subset of patients who responded to first-line treatment and subsequently received anticancer medication. RESULTS: The OS for patients initially randomized to first-line lenvatinib (versus first-line sorafenib) and who then received any subsequent anticancer medication was 20.8 vs. 17.0 months (hazard ratio [HR] 0.87; 95% CI 0.67-1.14). The OS for patients who initially received first-line lenvatinib (versus first-line sorafenib) and who did not receive any subsequent anticancer medication was 11.5 vs. 9.1 months (HR 0.90; 95% CI 0.75-1.09). Responders to first-line lenvatinib who received subsequent medication had a median OS of 25.7 months (95% CI 18.5-34.6); responders to first line-sorafenib who received subsequent medication had a median OS of 22.3 months (95% CI 14.6-not evaluable). CONCLUSIONS: In this post hoc analysis of all patients in the REFLECT study who received subsequent anticancer medication, OS was increased compared with patients who did not receive any subsequent anticancer medication. In a subset analysis of responders who had received subsequent anticancer medication, use of first-line lenvatinib led to a slightly longer median OS; more research is needed on the benefits of using first-line lenvatinib compared with sorafenib.

Colesevelam improved lipoprotein particle subclasses in patients with prediabetes and primary hyperlipidaemia.

BACKGROUND: A randomised, double-blind, placebo-controlled study evaluated lipid- and glucose-lowering effects of colesevelam in patients with prediabetes and primary hyperlipidaemia. We report the effect of colesevelam on lipoprotein particle concentration and particle size (determined by nuclear magnetic resonance spectroscopy) in these patients. METHODS: Adults with prediabetes (World Health Organization criteria), low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥2.6 mmol/L) and triglycerides < 500 mg/dL (<5.6 mmol/L) were randomised to colesevelam 3.75 g/day or placebo for 16 weeks. The intent-to-treat population comprised 103 colesevelam and 106 placebo recipients. RESULTS: At the end of the study, mean reduction from baseline in total LDL particle concentration was significantly greater with colesevelam versus placebo (mean treatment difference: -113 nmol/L; p = 0.02). Increases in total very low-density lipoprotein particle concentration (VLDL-P) and high-density lipoprotein particle concentration (HDL-P) did not differ significantly between the groups; however, with colesevelam versus placebo, there were significantly (p < 0.05) greater increases in large and medium VLDL-P and large HDL-P and reductions in small VLDL-P. Mean size increases were significantly greater with colesevelam for VLDL (mean treatment difference: 5.3 nm; p < 0.0001) and HDL (0.1 nm; p = 0.002). CONCLUSIONS: Colesevelam improved the overall atherogenic lipoprotein profile in adults with prediabetes and primary hyperlipidaemia, despite potentially less favourable changes in VLDL particles.

Initial combination therapy with metformin plus colesevelam improves lipoprotein particles in patients with early type 2 diabetes mellitus.

BACKGROUND: The bile acid sequestrant colesevelam has been shown to significantly reduce low-density lipoprotein particle concentration (LDL-P) in adults with primary hyperlipidemia or type 2 diabetes mellitus (T2DM). OBJECTIVE: To assess the effect of initial combination therapy with metformin plus colesevelam on lipoprotein particles in patients with T2DM (secondary efficacy variables). METHODS: This 16-week, randomized, double-blind, placebo-controlled study enrolled drug-naïve adults with T2DM, glycated hemoglobin 6.5%-10.0%, low-density lipoprotein cholesterol (LDL-C) ≥100 mg/dL, and triglycerides <500 mg/dL. Patients were randomized 1:1 to either open-label metformin (titrated to 1700 mg/day) plus double-blind colesevelam 3.75 g/day or open-label metformin plus double-blind placebo. RESULTS: In total, 286 patients were randomized (metformin plus colesevelam [n = 145]; metformin plus placebo [n = 141]). Compared with metformin plus placebo, the combination of metformin plus colesevelam significantly reduced LDL-C (mean treatment difference: -16.3%), total cholesterol (-6.1%), non-high-density lipoprotein cholesterol (-8.3%), and apolipoprotein (apo) B (-8.0%) and significantly increased triglycerides (median treatment difference: 18.6%) and apoA-I (mean treatment difference: 4.4%; all P < .001). Metformin plus colesevelam significantly reduced total LDL-P (mean treatment difference: absolute change -186 nmol/L [percent change -11.7%]; both P < .0001), largely attributable to a reduction in small LDL-P, and increased total very-low-density lipoprotein particle concentration (mean treatment difference: absolute change 6 nmol/L; P = .03 [percent change 8.3%; P = .06]) and total high-density lipoprotein particle concentration (1.0 µmol/L; P = .03 [4.5%; P = .01]) versus metformin plus placebo. CONCLUSION: Initial combination therapy with metformin plus colesevelam improved the atherogenic lipoprotein profile of patients with early T2DM by significantly reducing LDL-P. ClinicalTrials.gov identifier: NCT00570739.

Initial combination therapy with metformin plus colesevelam in drug-naïve Hispanic patients with early type 2 diabetes.

OBJECTIVE: To evaluate initial combination therapy with metformin plus colesevelam in drug-naïve Hispanic patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Patients self-identified as Hispanic from a previous study were included in this exploratory post hoc analysis. Patients were randomized to metformin plus colesevelam or metformin plus placebo. The primary efficacy parameter was the mean change in glycated hemoglobin (HbA1c) levels from baseline. RESULTS: Metformin plus colesevelam had a greater mean HbA1c reduction (-1.2 ± 0.1%) than metformin plus placebo (-0.8 ± 0.1%; P = 0.001) from mean baselines of 7.7% and 7.6%, respectively. Low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein (apo) B levels were also reduced (P < 0.0001 for all), while triglyceride (P < 0.0001) and apoA-I (P < 0.05) levels were increased with metformin plus colesevelam treatment compared with metformin plus placebo. With metformin plus colesevelam versus metformin plus placebo, more patients achieved an HbA1c of < 7.0% (75% vs 56%) and LDL-C of < 100 mg/dL (49% vs 14%; both P < 0.05). CONCLUSION: Metformin plus colesevelam may be an effective initial treatment option for Hispanic patients with early type 2 diabetes mellitus.

Clinical effects of colesevelam in Hispanic subjects with primary hyperlipidemia and prediabetes.

OBJECTIVE: To evaluate the efficacy and safety of colesevelam in Hispanic subjects with primary hyperlipidemia and prediabetes. MATERIALS AND METHODS: A 16-week, randomized, double-blind, placebo-controlled, multinational study evaluating colesevelam in participants with primary hyperlipidemia (low-density lipoprotein cholesterol [LDL-C] level ≥ 100 mg/dL) and prediabetes (fasting plasma glucose level ≥ 110 to ≤ 125 mg/dL, or 2-hour postload glucose level ≥ 140 to < 200 mg/dL during an oral glucose tolerance test) was conducted between January 14, 2008 and April 3, 2009. Participants were randomized 1:1 to colesevelam 3.75 g/day or placebo. The primary efficacy endpoint was mean change from baseline in LDL-C level with colesevelam compared with placebo. Participants who self-identified as Hispanic during enrollment were included in this exploratory analysis evaluating the efficacy of colesevelam in Hispanics with primary hyperlipidemia and prediabetes. RESULTS: From a total of 216 subjects with primary hyperlipidemia and prediabetes, 153 Hispanics were included in this post hoc analysis; 77 subjects were randomized to colesevelam and 76 subjects were randomized to placebo. At week 16, LDL-C levels were significantly reduced with colesevelam compared with placebo (mean treatment difference, -19.4%; P < 0.0001). Achievement of LDL-C level < 100 mg/dL was more frequent with colesevelam than with placebo (27% vs 11%; P = 0.002). In addition, significant mean reductions in non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B levels (P ≤ 0.0002 for all), and a significant median increase in triglyceride levels (P = 0.003), were seen with colesevelam compared with placebo. At study end, there was a significant mean reduction in glycated hemoglobin levels and median reduction in fasting plasma glucose levels with colesevelam compared with placebo (P ≤ 0.02 for both). A fasting plasma glucose level < 100 mg/dL was achieved in 44% of colesevelam recipients compared with 23% of placebo recipients (P < 0.05). Overall, colesevelam was well tolerated. CONCLUSION: Colesevelam may be a treatment option for Hispanic subjects with primary hyperlipidemia and prediabetes, mainly to reduce LDL-C levels, with added beneficial effect on glucose levels. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT00570739.

The effect of colesevelam hydrochloride on insulin sensitivity and secretion in patients with type 2 diabetes: a pilot study.

BACKGROUND: This study evaluated the effect of colesevelam hydrochloride on insulin sensitivity, potential binding to glucose, and chronic effect(s) on fasting and postprandial glucose and insulin in patients with type 2 diabetes mellitus. METHODS: Patients meeting inclusion criteria were withdrawn from all antidiabetes agents for 2 weeks and randomized to colesevelam 3.75 grams/day (n = 17) or placebo (n = 18) for 8 weeks. Hyperinsulinemic-euglycemic clamp studies were performed at baseline (week -1) and weeks 2 and 8. A meal tolerance test was conducted at weeks -1, 0, 2, and 8. The meal tolerance test and study drug were coadministered at week 0 to assess the direct effect of colesevelam on glucose absorption. RESULTS: Insulin sensitivity as measured by the insulin clamp method did not change, but the Matsuda Index, a measure of whole-body insulin sensitivity calculated from postmeal tolerance test glucose and insulin levels, increased significantly within the colesevelam group from baseline to week 8 with last observation carried forward (P = 0.020). The postprandial area under the curve for glucose decreased with colesevelam versus placebo at weeks 2 and 8 with last observation carried forward (P = 0.012 and P = 0.061, respectively); the area under the curve for insulin did not decrease in concert with the decrease in area under the curve for glucose at week 2 (P = 0.585). Colesevelam had no effect on postmeal tolerance test glucose levels at week 0. CONCLUSIONS: These results suggest that colesevelam has no effect on peripheral insulin sensitivity or glucose absorption, but may improve glucose control by improving whole-body insulin sensitivity, although not by an acute effect on glucose absorption. CLINICAL TRIAL IDENTIFIER: NCT00361153.

Colesevelam hydrochloride to treat hypercholesterolemia and improve glycemia in prediabetes: a randomized, prospective study.

OBJECTIVE: To assess the effect of the bile acid sequestrant colesevelam hydrochloride in patients with hypercholesterolemia and prediabetes. METHODS: In this 16-week, randomized, double-blind study, adults with untreated prediabetes (2-hour postoral glucose tolerance test [OGTT] glucose > or =140 to 199 mg/dL, fasting plasma glucose [FPG] > or =110 to 125 mg/dL, or both), low-density lipoprotein cholesterol (LDL-C) > or =100 mg/dL, and triglycerides <500 mg/dL were randomly assigned to receive colesevelam (3.75 g/d) or placebo. The primary end point was percent change in LDL-C from baseline to week 16 with last observation carried forward. Secondary end points included change in FPG, hemoglobin A1c (A1C), and 2-hour post-OGTT glucose level from baseline to week 16 and attainment of LDL-C and FPG targets. RESULTS: In total, 216 patients were randomized (colesevelam, 108; placebo, 108). In comparison with placebo, colesevelam significantly reduced LDL-C (mean treatment difference, -15.6%), non-high-density lipoprotein cholesterol (-9.1%), total cholesterol (-7.2%), apolipoprotein B (-8.1%) (P<.001 for all the foregoing), FPG (median, -2.0 mg/dL; P = .02), and A1C (mean, -0.10%; P = .02). Colesevelam did not significantly change 2-hour post-OGTT glucose (-1.9 mg/dL; P = .75) or high-density lipoprotein cholesterol (-0.5%; P = .80). In addition, colesevelam significantly increased triglyceride levels relative to placebo (median, 14.3%; P<.001). The proportion of patients achieving target levels with colesevelam versus placebo, respectively, was as follows: LDL-C <100 mg/dL (29% versus 11%; P<.001), A1C <6.0% (37% versus 25%; P = .05), FPG <110 mg/dL (48% versus 56%; P = .97), and normalization of glucose (FPG <100 mg/dL [40% versus 23%; P = .06]). Colesevelam had a weight-neutral effect and was well tolerated. CONCLUSION: Colesevelam is an option for managing the lipid profile and normalizing glucose levels in patients with hypercholesterolemia and prediabetes. Further study is warranted to determine whether colesevelam slows or prevents progression of prediabetes to type 2 diabetes.

Initial combination therapy with metformin and colesevelam for achievement of glycemic and lipid goals in early type 2 diabetes.

OBJECTIVE: To evaluate the efficacy and safety of initial combination therapy with metformin plus colesevelam in patients with early type 2 diabetes. METHODS: In this 16-week, randomized, double-blind, placebo-controlled study, adults with type 2 diabetes (hemoglobin A1c [A1C] values of 6.5% to 10.0%) and hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] levels > or =100 mg/dL) were randomly assigned (1:1) to colesevelam (3.75 g/d) or placebo in combination with open-label metformin (850 mg/d; uptitrated at week 2 to 1,700 mg/d). The primary efficacy evaluation was change in A1C from baseline to study end (week 16 with last observation carried forward). RESULTS: In total, 286 patients were randomized: metformin/colesevelam (n = 145) or metformin/placebo (n = 141). Mean A1C was reduced by 1.1% with metformin/colesevelam (from 7.8% at baseline to 6.6% at study end) and by 0.8% with metformin/placebo (from 7.5% to 6.7%), resulting in a treatment difference of -0.3% at study end (P = .0035). In addition, metformin/colesevelam significantly reduced LDL-C (-16.3%), total cholesterol (-6.1%), non-high-density lipoprotein cholesterol (-8.3%), apolipoprotein B (-8.0%), and high-sensitivity C-reactive protein (-17%) and increased apolipoprotein A-I (+4.4%) and triglycerides (+18.6%) versus metformin/placebo (P<.01 for all). The proportions of patients who achieved recommended goals with metformin/colesevelam versus metformin/placebo, respectively, were as follows: A1C <7.0% (67% versus 56% [P = .0092]), LDL-C <100 mg/dL (48% versus 18% [P<.0001]), and composite A1C <7.0% + LDL-C <100 mg/dL (40% versus 12% [P<.0001]). Safety and tolerability were similar between the treatment groups. CONCLUSION: Metformin plus colesevelam may be a valid option for initial therapy to achieve glycemic and lipid goals safely in early type 2 diabetes.

Concomitant reduction in low-density lipoprotein cholesterol and glycated hemoglobin with colesevelam hydrochloride in patients with type 2 diabetes: a pooled analysis.

Colesevelam hydrochloride (COL), a bile acid sequestrant indicated as an adjunct to diet and exercise for reducing low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia, was shown in a pilot study to reduce both glycated hemoglobin (HbA1c) and LDL-C in patients with type 2 diabetes mellitus (T2DM). Three double-blind, placebo-controlled trials in T2DM have now independently confirmed the HbA1c and LDL-C reductions with COL. In each of the primary studies, a significant mean treatment difference in HbA1c (-0.54%, -0.50%, and -0.54%) and LDL-C (-15.9%, -12.8%, and -16.7%) resulted from the addition of 3.75 grams/day of COL to existing metformin, insulin, or sulfonylurea-based therapy, respectively, in patients with T2DM inadequately controlled on their current antidiabetic regimen. Here we report the results of a pooled analysis of data for the 1018 patients included in the three primary studies. By study end, HbA1c, fasting plasma glucose (FPG), LDL-C, total cholesterol (TC), non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hsCRP) were significantly reduced with COL versus placebo. Triglyceride (TG) and ApoA-I were significantly increased in the COL group relative to placebo. HDL-C did not change in either group, and the between-group treatment difference was small and not significant. Results of this pooled analysis are consistent with results reported previously in each of the primary COL studies and indicate that the HbA1c and LDL-C-lowering effects of COL are consistent, occurring regardless of whether COL is added to metformin, insulin, or sulfonylurea-based therapy. In conclusion, COL represents a novel therapeutic option by significantly lowering both LDL-C and HbA1c in patients with T2DM, two important treatment goals to forestall vascular complications.

Rationale and design of a clinical trial to evaluate metformin and colesevelam HCl as first-line therapy in type 2 diabetes and colesevelam HCl in prediabetes.

OBJECTIVE: The complications of type 2 diabetes mellitus (DM) can begin early in the progression from impaired glucose tolerance to type 2 DM. Metformin is recommended as initial drug therapy for managing hyperglycemia in type 2 DM. The bile acid sequestrant colesevelam hydrochloride (HCl) is approved in the United States for glycemic control in adults with type 2 DM. Colesevelam HCl improves glycemic control and reduces low-density lipoprotein-cholesterol in patients inadequately controlled on metformin-, sulfonylurea-, or insulin-based therapy. This trial is designed to evaluate whether initial therapy with metformin + colesevelam HCl provides greater glucose control and additional lipid and lipoprotein benefits, as compared to metformin alone in drug-naïve patients with type 2 DM, and whether treatment with colesevelam HCl has a beneficial effect on lipid and glucose levels in drug-naïve patients with impaired glucose tolerance and/or impaired fasting glucose (prediabetes). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, drug-naïve patients with type 2 DM will be randomized 1 : 1 to metformin + colesevelam HCl or metformin + matching placebo, while those with prediabetes will be randomized 1 : 1 to colesevelam HCl or placebo, for 16 weeks of treatment. The primary efficacy endpoint will be change in glycosylated hemoglobin (HbA(1c)) in patients with type 2 DM and change in low-density lipoprotein-cholesterol levels in patients with prediabetes. CONCLUSION: A potential limitation is that there is no direct comparator for the dual glucose- and lipid-lowering effect of colesevelam HCl in the prediabetes cohort. However, results of this trial will help to define the extent to which colesevelam HCl can help improve cardiometabolic risk factors for complications of type 2 DM in the first-line environment, and will also indicate the extent to which early intervention with colesevelam HCl can help to correct metabolic abnormalities associated with prediabetes.